PROMISE

Published

Douglas PS, et al. "Outcomes of anatomical versus functional testing for coronary artery disease". The New England Journal of Medicine. 2015. 372(14):1291-1300.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with new stable angina, does evaluation with coronary computed tomographic angiography (CCTA) result in improved outcomes compared with evaluation using functional testing?

Bottom Line

Evaluation of new stable angina with coronary computed tomographic angiography (CCTA) compared to functional testing did not result in improvement in the composite outcome of death from any cause, nonfatal myocardial infarction, hospitalization for unstable angina, or major procedural complications.

Major Points

Anatomical testing with coronary computed tomographic angiography (CCTA) to detect coronary artery disease is a promising tool in evaluating stable angina, with the potential to identify prognostically significant lesions that would be missed by functional testing (nuclear stress testing, stress echocardiography, or exercise ECG). Despite its promise, CCTA had not previously been assessed for hard clinical outcomes among persons with new stable angina.

Published in 2015, the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial was a pragmatic comparative effectiveness trial that randomized 10,003 patients with new angina to CCTA or a functional test as workup. There was no difference in the composite primary outcome of all-cause mortality, nonfatal MI, UA hospitalization, or major procedural complication between groups (CCTA 164 vs. functional testing 151; HR 1.04; 95% CI 0.83-1.29; P=0.75). There were fewer invasive catheterizations showing no obstructive CAD in the CCTA group, however (3.4% vs. 4.3%; P=0.02).

This study is in contrast to the 2018 SCOT-HEART trial's 5-year results, which found a decrease in the composite end point of death from CHD or nonfatal myocardial infarction in the CCTA group compared to standard of care, driven by nonfatal myocardial infarction. Unlike the PROMISE study, the patients in the CCTA group of SCOT-HEART were more likely to have started preventative therapies compared to standard of care. As noted in the accompanying editorial, it is unknown whether either functional testing or anatomical testing improves outcomes compared to medical therapy alone in these patients, as neither study was designed to address that question.

Guidelines

2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR chest pain evaluation and diagnosis (adapted)

• With acute chest pain:
  • If 30 day risk of death or MACE is <1%, designate as low-risk (COR 1, LOE B-NR)
  • If low risk, it is reasonable to discharge home without admission or urgent cardiac testing (COR 2a, LOE B-R)
  • If intermediate risk and no known CAD:
    • After negative/inconclusive evaluation for ACS (e.g., in ED), CCTA is useful for exclusion of atherosclerotic plaque and obstructive CAD as an anatomic test (COR 1, LOE A)
    • If eligible for cardiac testing, exercise ECG, stress echo, stress PET/SPECT MPI, or stress CMR is useful for diagnosis of ischemia (COR 1, LOE B-NR)
    • If mild-moderate ischemia on current stress testing or stress testing in prior year, and no known CAD was established in prior anatomic testing, invasive coronary angiography is recommended as an anatomic test (COR 1, LOE C-EO)
    • If mildly abnormal stress test results in the prior year, CCTA is resonable for diagnosing obstructive CAD (COR 2a, LOE C-LD)

Design

• Multicenter, randomized, controlled trial
• N=10,003
  • CCTA (n=4996)
  • Functional testing (n=5007)
• Setting: 193 cardiology, radiology, primary care, urgent care, and anesthesiology sites in Canada and the United States
• Enrollment: 2010-2013
• Median follow-up: 25 months (all were followed up through Oct 31, 2014)
• Analysis: Intention-to-treat
• Primary outcome: All-cause mortality, nonfatal MI, UA hospitalization, major procedural complication

Population

Inclusion Criteria

• New or worsening chest pain or equivalent symptoms suspicious for coronary artery disease
• No prior cardiac evaluation for this episode of symptoms
• Planned noninvasive testing for diagnosis
• Men aged ≥55 years and women aged ≥65 years
• If a man aged 45-54 a woman aged 50-64, must have ≥1 of the following:
  • Diabetes requiring medical treatment
  • PAD with peripheral artery stenosis ≥50%, treated medically or invasively
  • Cerebrovascular disease, defined as documented carotid stenosis ≥50%, treated medically or invasively
  • Current use of tobacco
  • Hypertension
  • Ankle brachial index <0.9
  • Dyslipidemia
• Serum creatinine ≤1.5 mg/dL in prior 90 days
• Negative urine/serum pregnancy test result for female subjects of childbearing potential

Exclusion Criteria

• Diagnosed or suspected acute coronary syndrome requiring hospitalization or urgent or emergent testing; elevated troponin or CK-MB
  • outpatients who have completed a rule-out ACS protocol were still eligible if they had 2 sets of negative biomarkers and a non diagnostic or normal EKG
• Hemodynamically or clinically unstable condition (systolic BP < 90 mm Hg, severe atrial or ventricular arrhythmias, or persistent resting chest pain felt to be ischemic despite adequate therapy)
• Known coronary artery disease with clinical history of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, or any angiographic evidence of coronary artery disease >/= 50% lesion in a major epicardial vessel
• Any invasive coronary angiography or noninvasive anatomical or functional cardiovascular test for detection of coronary artery disease within previous 12 months (+/- 30 days)
• Known significant congenital, valvular (moderate or greater), or cardiomyopathy process (hypertrophic cardiomyopathy or LV ejection fraction < 40%) that could explain cardiac symptoms.
• Contraindication to CCTA, including allergy to contrast or pregnancy
• Any other contraindications that would preclude performing a CCTA per local site practice, such as >/= 1 of the following:
  • Inability to receive beta-blockers if heart rate is > 65 beats/min
  • Agatston score > 800
  • BMI > 40 kg/m^2
  • Cardiac arrhythmia
• Life expectancy < 2 years
• Unable to provide written informed consent or participate in long-term follow-up

Baseline Characteristics

From the CCTA group

• Demographics: Age 61 years, female sex 52%, racial or ethnic minority 24%
• Risk factors: Hypertension 65%, diabetes 21%, dyslipidemia 67%, FH premature CAD 33%, PAD or cerebrovascular disease 5%, CAD risk equivalent 25%, metabolic syndrome 37%, active or former smoker 51%, sedentary lifestyle 49%, depression 20%
  • Without any risk factors: 2.5%
  • Count of risk factors: 2.4
• Diamond and Forrester and CASS risk score: 53.4 Note: this is out of 100, higher scores indicate greater likelihood of CAD
• Meds: Beta blocker 25%, ACE or ARB 44%, statin 46%, ASA 45%
• Presenting symptom: Chest pain 74%, DOE 14%, other 12%
• Angina type: Typical 12%, atypical 78%, non-anginal pain 11%

Interventions

• Randomized to a group
  • CCTA
  • Functional-testing group - Exercise ECG, exercise or pharmacologic nulcear stress testing, or stress echocardiography
• Stratified according to study site and choice of intended functional test prior to randomization
• All subsequent decisions were made by local physician performing and interpreting tests
• Follow-up visits at 60 days at study sites and centrally by telephone or mail every 6 months from randomization for a minimum of 1 year

Outcomes

Comparisons are CCTA vs. functional testing.

Primary Outcomes

All-cause mortality, nonfatal MI, UA hospitalization, major procedural complication

164 vs. 151 (HR 1.04; 95% CI 0.83-1.29; P=0.75)

Secondary Outcomes

Primary endpoint plus catheterization showing no obstructive CAD

332 vs. 353 (HR 0.91; 95% CI 0.78-1.06; P=0.22)

All-cause mortality or nonfatal MI

104 vs. 112 (HR 0.88; 95% CI 0.67-1.15; P=0.35)

All-cause mortality, nonfatal MI, or hospitalization for unstable angina

162 vs. 148 (HR 1.04; 95% CI 0.84-1.31; P=0.70)

Additional Outcomes

Invasive catheterization showing no obstructive CAD

3.4% vs. 4.3% (P=0.02)

Median cumulative radiation exposure in all procedures ≤90 days after randomization (in mSv)

10.0 vs 11.3 (P<0.001)

Intended testing pre-randomization

Nuclear stress testing: 10.1 vs. 12.6 (P<0.001)

Stress echo: 10.6 vs. 0 (P<0.001)

Exercise ECG: 8.5 vs. 0 (P<0.001)

Criticisms

• There were fewer events than expected, which may have underpowered the study to detect a difference between the groups if present.

Funding

National Heart, Lung, and Blood Institute at the NIH